Journal of Pain Research
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The effect of hypnosis on pain and peripheral
blood flow in sickle-cell disease: a pilot study
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Ravi R Bhatt 1
Sarah R Martin 1
Subhadra Evans 2
Kirsten Lung 1
For personal use only.
Thomas D Coates 3,4
Lonnie K Zeltzer 1
Jennie C Tsao 1
1
UCLA Pediatric Pain and Palliative
Care Program, Division of
Hematology-Oncology, Department
of Pediatrics, David Geffen School
of Medicine at UCLA, Los Angeles,
CA, USA; 2School of Psychology,
Deakin University, Geelong, VIC,
Australia; 3Department of Pediatrics,
Keck School of Medicine, University
of Southern California, 4Children’s
Center for Cancer and Blood
Diseases, Children’s Hospital Los
Angeles, Los Angeles, CA, USA
Correspondence: Ravi R Bhatt
UCLA Pediatric Pain and Palliative Care
Program, Department of Pediatrics,
David Geffen School of Medicine at
UCLA, 10833 Le Conte Ave – MDCC
22-464, Los Angeles, CA 90095, USA
Email ravibhatt@mednet.ucla.edu
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http://dx.doi.org/10.2147/JPR.S131859
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ORIGINAL RESEARCH
This article was published in the following Dove Press journal:
Journal of Pain Research
14 July 2017
Number of times this article has been viewed
Background: Vaso-occlusive pain crises (VOCs) are the “hallmark” of sickle-cell disease (SCD)
and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system
activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk
for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate
vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients
with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular
responses are unknown. The current study assessed the effects of hypnosis on peripheral blood
flow, pain threshold, tolerance, and intensity in adults with and without SCD.
Subjects and methods: Fourteen patients with SCD and 14 healthy controls were included.
Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis ses-
sion. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis
were examined.
Results: A single 30-minute hypnosis session decreased pain intensity by a moderate amount
in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control
group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral
blood flow and a greater increase in blood flow following hypnosis than controls.
Conclusion: Given that peripheral vasoconstriction plays a role in the development of VOC,
current findings provide support for further laboratory and clinical investigations of the effects
of cognitive–behavioral neuromodulatory interventions on pain responses and peripheral vas-
cular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral
vasodilation during both the anticipation and experience of pain in patients with SCD. These
findings indicate a need for further examination of the effects of hypnosis on pain and vascular
responses utilizing a randomized controlled trial design. Further evidence may help determine
unique effects of hypnosis and potential benefits of integrating cognitive–behavioral neuro-
modulatory interventions into SCD treatment.
Keywords: sickle-cell disease, pain, hypnosis, blood
Introduction
Sickle-cell disease (SCD) affects up to 100,000 Americans at a rate of one of every
500 African-American births.1 Vaso-occlusive pain crises (VOCs) are considered the
“hallmark” of SCD. VOCs occur frequently and may lead to development of chronic
pain, such that 30% of sampled patients with SCD have reported pain nearly every
day.1 It has been proposed that continuous allostatic stress load (eg, recurring VOCs)
can initiate a cascade of physiological changes in patients who experience recurrent
pain.2 Enhanced sympathetic nervous system activation, parasympathetic nervous
Journal of Pain Research 2017:10 1635–1644 1635
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 Bhatt et al
system withdrawal, and subsequent peripheral vaso-occlusion
in individuals with SCD3 result in hypoxic tissue damage,
which if recurrent may ultimately lead to changes to the
peripheral and central nervous systems. Indeed, transgenic
sickle mice exhibit hyperalgesia and neuronal hypersensitiv-
ity and individuals with SCD show hypersensitivity (lower
pain thresholds) to thermal stimuli,4 providing support for the
hypothesis that changes in peripheral and central neuronal
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sensory signaling may lead to changes in pain responsive-
ness.5,6 If this hypothesis is validated, SCD patients with
frequent7 VOCs may be at higher risk for the development
of altered pain-response mechanisms and thus at higher risk
for the development of chronic pain. Therefore, examination
of interventions that may address factors associated with the
initiation of VOCs (eg, stress, pain, peripheral blood flow)
is needed.
Neuromodulatory interventions target cortical pain
modulation and have been shown to have a favorable effect
For personal use only.
on central and peripheral physiological processes related to
the experience of acute and chronic pain;8,9 however, limited
data exist on the effect of neuromodulatory interventions on
mechanisms underlying VOCs (ie, microvascular stress/pain
responses) in patients with SCD. Engagement in hypnosis,
a cognitive-based neuromodulatory intervention, has been
associated with decreases in acute and chronic pain.8 Specifi-
cally, engagement in hypnosis is associated with changes in
central neuromodulatory and autonomic processes.9–13
Despite limited studies in SCD samples, preliminary
evidence suggests that hypnosis may be a promising inter-
vention to mitigate pain and the acute-stress response. One
study described patients with SCD reporting less pain overall
as well as during VOCs following a hypnosis intervention.14
A case study of a longitudinal hypnosis intervention in two
adolescents with SCD reported that the adolescents had a
feeling of overall warmth and a flushed appearance, presumed
to be associated with peripheral vasodilation.15 Other studies
reported preliminary evidence of hypnosis-induced vasodila-
tation in healthy controls and other pain conditions.14,15 These
results suggest that hypnosis may be a beneficial ­cognitive–
behavioral intervention for individuals with SCD. While
prior studies have shown promise for hypnosis as a clinical
tool for pain control in SCD, the mechanisms underlying the
effects of hypnosis on acute pain in this population remain
unknown. Because the clinical setting provides significant
variability in pain experiences, context, and responses, a
study of mechanisms of the effects of hypnosis on acute
pain in patients with SCD is best studied in the controlled
setting of a psychophysiological pain laboratory. Inclusion
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of a comparison non-SCD control group can further provide
evidence on responses that may be unique to patients with
SCD. Therefore, the objective of the current study was to
assess the effects of hypnosis on acute experimental pain
responses and the corresponding responses in microvascu-
lature in adults with and without SCD.
Specific aims and hypotheses
The first aim of this pilot study was to assess whether base-
line pain responses (ie, pain threshold, tolerance, intensity)
and peripheral blood flow differed across patients with SCD
and race-matched healthy controls. The second aim was to
examine the effect of a brief hypnotic intervention on acute
experimental pain responsiveness during a thermal pain task,
as assessed by pain threshold, tolerance, and intensity. The
third aim was to determine the effects of hypnosis on changes
in peripheral blood flow during anticipation of the pain task
and during the pain task itself. Finally, the fourth aim was
to determine if the effect of hypnosis on pain responses and
blood flow differed across groups.
We hypothesized that patients with SCD would have
lower peripheral blood flow at baseline and demonstrate lower
pain thresholds and tolerance and higher pain intensity. We
hypothesized that in both groups, pain threshold and toler-
ance would increase and pain intensity would decrease after
hypnosis. We also hypothesized that peripheral blood-flow
amplitude would increase in both groups during the anticipa-
tion and experience of the pain tasks following the hypnosis
intervention. Finally, due to already present vasoconstriction
and reduced blood flow, we hypothesized that patients with
SCD would experience more benefit from hypnosis and thus
exhibit a greater change in blood flow following hypnosis. In
addition, we expected that patients with SCD would demon-
strate a greater increase in pain threshold and tolerance and
decrease in pain intensity following hypnosis compared to
healthy controls.
Subjects and methods
All procedures and methods of the current study were
approved by the Medical Institutional Review Board of the
University of California – Los Angeles. This trial is registered
with ClinicalTrials.gov (NCT02620488).
Participants
Participants with SCD (n=14, eleven females, mean age 34
years, SD 12.88) and without SCD (n=14, eleven females,
mean age 37.23 years, SD 17.34) were recruited from vari-
ous locations in the greater Los Angeles area, including the
Journal of Pain Research 2017:10
 Dovepress
Cayenne Wellness Center and Children’s Foundation, and
various community SCD meetings in Los Angeles. Inclusion
criteria for the participants with SCD were a confirmed diag-
nosis of SS hemoglobin, SC hemoglobin, or S-thalassemia
hemoglobin. Inclusion criteria for the control population
were healthy individuals (ie, no chronic illness diagnosis)
whose race matched that of the SC patients. Exclusion criteria
included any neurologic disorder that affected sensation, skin
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abnormalities/abrasions over the site of stimulus application,
and any acute or chronic illness that may have impaired
safety or lab performance. All participants were screened
via telephone to determine eligibility. We know of only one
study looking at changes in peripheral blood flow in disease
populations,16 and various studies investigating peripheral
blood flow following hypnotic suggestions.14,17
We chose our sample size to assess feasibility of the cur-
rent protocol and to see if there was any effect on a clinically
meaningful outcome that has been specifically implicated
For personal use only.
in the genesis of VOCs, and our sample comparable to past
studies looking at hypnosis and peripheral blood flow.
Procedure
All procedures were approved by the Institutional Review
Board of the University of California, Los Angeles and were
conducted at the Pediatric Pain and Palliative Care Program
Laboratory. The experimenter and the participant were seated
in the same room. The participant first provided written con-
sent and completed questionnaires. Next, a pulse-oximetry
transducer was placed on the participant’s left thumb to assess
peripheral blood flow. The participant sat quietly for 3 min-
utes, during which baseline peripheral blood-flow data were
collected. Following the baseline period, the experimenter
verbally announced, “In a minute, pain task 1 will begin”,
which marked the start of the pain-anticipation period that
lasted approximately 1 minute. The first set of pain tasks
(referred to pre-hypnosis tasks) were then conducted and
pain threshold and tolerance assessed. This was followed by
a 3-minute recovery, or washout period, and then followed
Baseline Anticipation
Pain intensity
Washout
Figure 1 Summary of study phases before and after hypnosis.
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Hypnosis on pain and blood flow in SCD
by assessing pain intensity. After the three pain tasks had
been completed, a psychologist trained in medical hypnosis
was then brought into the room to engage the participant in
a 30-minute hypnosis session. After the psychologist had
delivered hypnotic suggestions for analgesia (referred to as
post-hypnosis), the three pain tasks were readministered in
the same order as before hypnosis (with a 3-minute washout
period following assessment of pain threshold). During the
second pain task, the participant was receiving booster sugges-
tions from the psychologist. The anticipation period before the
application of the pain stimulus was investigated because it is
known that the anticipation of pain has influence over activity
in the somatosensory cortex, and thus can influence the pain
experience itself and corresponding physiological responses.18
A summary of the study phases is depicted in Figure 1. At
the end of the laboratory session, the psychologist conducted
a brief exit interview and confirmed that the participant was
fully alert and able to function cognitively before leaving the
premises. Compensation was then provided.
Measures
Peripheral blood flow
Peripheral blood flow and the heat signal from the neurosen-
sory analyzer were collected continuously throughout the study
using the BioPac MP150 system and AcqKnowledge software
(version 3.9.0) so that the timing of all of the measurements
was synchronized. Continuous readings for SpO2, pulse rate,
and pulse waveform were monitored using the pulse-oximetry
transducer placed on the left thumb at 1,000 Hz. The average
blood-flow amplitude – defined by the distance from trough
to peak on photoplethysmography – during each study phase
was used for analyses. Blood-flow data were then normalized
so that parametric statistical tests could be performed, and thus
no unit is reported, as they were normalized.
Laboratory pain responsiveness
All nociceptive stimulation was applied using a TSA-II
neurosensory analyzer (Medoc Advanced Medical Systems,
Pain threshold Pain tolerance
Anticipation Washout
Hypnosis Repeat
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 Bhatt et al
Ramat Yishai, Israel). The TSA-II consists of a “thermode”
(30×30 mm) starting at a temperature of 32°C and reaching
a maximum temperature of 52°C to prevent tissue damage.
The thermode was placed on the participant’s right forearm
(brachioradialis muscle) just below the joint cavity and was
moved down 25.4 mm after each ramp was delivered. Each
participant was administered a set of pain tasks twice: before
and after hypnotic analgesia suggestions. Each set of pain
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tasks consisted of three pain tasks (ie, assessment of pain
threshold, pain tolerance, and pain intensity; see Figure 1
for illustration of study procedure). This procedure was
established in a previous study.19
Pain threshold and tolerance
The pain-threshold and -tolerance tasks consisted of six
heat ramps. Once the ramp started, temperature rose 1°C
per second. During the first three ramps, participants indi-
cated when they first perceived the stimulus to be painful,
For personal use only.
which was considered their pain threshold. During the
last three ramps, participants indicated when they could
no longer tolerate the pain (ie, pain tolerance). Then, the
threshold and tolerance ratings were averaged across all
six trials (three threshold and three tolerance trials), and
this value was used as the target temperature administered
during the third task.
Pain intensity
The third task consisted of two heat ramps delivered at the
aforementioned target temperature. Once the thermode
reached this temperature, the participant was asked to rate
his/her pain intensity on a 0–100 numeric rating scale (ie,
0 = no pain, 100 = worst pain possible). This value was clas-
sified as pain intensity.
Hypnosis intervention
After administration of the first set of pain tasks, the psy-
chologist greeted the patient. The participant was informed
about the facts and myths about medical hypnosis and was
provided an opportunity to ask questions. The hypnosis pro-
cedure was divided into five phases: 1) relaxation induction
to induce a narrowed focus of attention, 2) intensification
of the focused attention and involvement in imagery using
a “favorite place” suggestion, 3) pre-pain-task analgesic
suggestions for personally derived analgesic imagery, 4) pre-
and within-task blood-flow suggestions targeting improved
peripheral vasodilatation through imagery related to warming
and water flow, and 5) posttask posthypnotic suggestions for
continued comfort with an alert mind.
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Relaxation induction
After the introduction, the participant was encouraged to sit in
a relaxed, comfortable position with eyes closed, if so desired.
The participant was then invited to experience relaxation
imagery, involving relaxation throughout the body with such
suggestions as “Allowing all the muscles in the shoulders to
let go, relaxing, feeling the support of the chair, sinking into
the chair… letting all the tension drain out of the shoulders”.
Intensification
A deepening elevator exercise was then used, where the par-
ticipant was instructed to imagine going down in an elevator
and relaxing more deeply with each floor. This was followed
by instructions to imagine a favorite place, a place that evokes
feelings of relaxation and ease. The participant was invited to
experience the sights, smells, and textures of this favorite place,
eg, “… You inhale and smell all the delicious smells of your
favorite place. Perhaps it’s a beach, or a mountaintop. Somewhere
you’ve felt warm and safe and serene and content before. You
reach down and feel the ground. Is it sand slipping through the
fingers, or the coolness of new-grown grass? Let’s stay here, in
this place, for a few moments, while you soak in the sensations.”
Hypnotic analgesia – suggestion 1
Next, consistent with the study by Jensen,20 analgesia sug-
gestions were offered in which the participant was invited to
imagine his or her own personal pain analgesia. Suggestions
were offered for this personal analgesia to be experienced as
a favorite color, a cooling balm, a pill, or any other way the
subject desired. Feelings of relief and comfort were encour-
aged immediately following use of the analgesia.
Hypnotic analgesia and vasodilatory imagery –
suggestion 2
The pain tasks were then administered a second time, while
the hypnotherapist continued to support the participant in the
experience of relief and comfort, eg, “… perhaps imagining
feelings of relief throughout the arm, the arm feeling more
and more comfortable as the medicine spreads”. During the
pain task, the psychologist continued to provide booster sup-
port to enhance the effects hypnotic analgesia further, eg, “…
Now imagine the area of the arm experiencing heat, imagine
it being completely surrounded… or completely filled… with
a sensation of relief… a pleasant sensation of comfort … you
might like to picture feelings of relief spreading down the arm.
Noticing how naturally, how easily, you are able to make the
arm feel different and much more pleasant… even decreasing
sensations from that area; as if it were disappearing”.
Journal of Pain Research 2017:10
 Dovepress Hypnosis on pain and blood flow in SCD

Posthypnotic period r=–0.48, p=0.09) or pain tolerance (r=–0.47, p=0.09; r=0.11,

After the pain tasks had been completed, the psychologist
invited the participant to experience warm-bath imagery,
designed to evoke vasodilatory sensations for a 5- to 7-minute
posttask recovery period. Instructions included: “This bath,
just the right kind of warmth. The water soothing muscles,
opening the body, to relax. Such a calm, pleasant feeling. The
warm water like liquid therapy, melting away troubles, wash-
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p=0.7) in the SCD and control groups, respectively. Age was
associated with baseline peripheral blood flow in patients with
SCD (r=0.69, p=0.019), but not in controls (r=0.32, p=0.31).
Aim 1: baseline pain threshold, tolerance,
self-reported pain intensity, and blood
flow

ing away cares, allowing the body to relax into an even deeper
state of well-being”. The participant was then provided with
sufficient time to return to their normal state. A countdown
from 10 to 1 was used, with 1 being a state of full awareness
and alertness. The full script for the hypnosis procedure is
included in the Supplementary Material.
Data analysis
Shapiro–Wilk tests of normality were conducted on the
primary-outcome variables (blood flow, pain threshold, pain
For personal use only.
An independent-sample t-test revealed that there was no
difference in baseline pain threshold (t25.96=–0.07, d=0.03;
p=0.94), tolerance (t25.82=-0.25, d=0.09; p=0.81), or inten-
sity (t25.38=–0.75, d=0.29; p=0.457). The same test revealed
controls had higher peripheral blood flow during baseline
than patients with SCD (t21.17=2.54, d=1.01; p=0.019), but
there were no group differences during hypnosis (t19.14=1.61,
d=0.672; p=0.12). No other differences between groups were
found across tasks in blood flow. Means of each task across
groups are reported in Table 1.

tolerance, pain intensity) to determine appropriate statistical

tests. Natural log transformations were conducted to normal- Aim 2: effects of hypnosis on pain
ize abnormal pain-responsiveness data, but the data were
threshold, tolerance, and self-reported
resistant to transformation. As such, appropriate parametric
(ie, paired- or independent-sample t-tests) and nonparametric
pain intensity
Paired t-tests and Wilcoxon signed-rank tests were conducted
(ie, Wilcoxon signed-rank and Mann–Whitney U-tests) mean-
within groups to determine the effect of hypnosis on controls
difference tests were used for analyses that included normal
and patients with SCD for each task. Results revealed that
and abnormal variables, respectively. Independent-sample
t-tests were utilized to determine if baseline levels differed
across groups. Paired-sample mean-difference tests were Table 1 Laboratory pain sensitivity and peripheral blood flow
conducted to determine if there was a significant change in during each phase of the study

laboratory pain responses and blood-flow amplitude following Pain Controls (n=14) SCD (n=14)
hypnosis. To compare the effect of hypnosis on blood-flow Mean SD Mean SD
(°C) (°C)
amplitude across groups, the change in amplitude following
Pre-hypnosis pain threshold 43.56 3.95 43.86 3.93
hypnosis was determined by subtracting the mean amplitude Pre-hypnosis pain tolerance 47.12 2.83 47.39 2.57
during hypnosis from the amplitude value during each post- Pre-hypnosis pain intensity 31.68 22.44 38.64 26.27
hypnosis task. Independent-sample t-tests were then used to Post-hypnosis pain threshold 45.9 3.81 44.45 3.71
Post-hypnosis pain tolerance 48.48 1.98 47.7 3
compare change in blood-flow amplitude across groups. All
Post-hypnosis pain intensity 18.57 18.26 33.46 28.23
significance testing was conducted at α=0.05. Parametric test-
Blood flow Controls (n=13) SCD (n=11)
ing used Cohen’s d as the effect size (small = 0.2, medium =
Mean SD Mean SD
0.5, large = 0.8).19 Nonparametric testing used Pearson’s r as
Baseline** 0.82 0.07 0.76 0.05
the effect size (small = 0.1, medium = 0.3, large = 0.5).20 All Pre-hypnosis anticipation 1 0.81 0.08 0.76 0.05
analyses were conducted in RStudio (version 3.2.1). Pre-hypnosis pain task 1 0.82 0.05 0.77 0.05
Pre-hypnosis anticipation 2 0.81 0.09 0.76 0.08
Pre-hypnosis pain task 2* 0.81 0.06 0.75 0.08
Results Hypnosis 0.8 0.05 0.76 0.06
Preliminary results Post-hypnosis anticipation 1* 0.79 0.06 0.82 0.05
The sample consisted of 14 total patients with SCD (eleven Post-hypnosis pain task 1 0.79 0.05 0.79 0.07
Post-hypnosis anticipation 2 0.77 0.09 0.82 0.09
females, mean age 34 years, SD 12.88) and 14 healthy controls Post-hypnosis pain task 2 0.78 0.08 0.79 0.07
(eleven females, mean age 37.23 years, SD 17.34). Age was Note: *p<0.05; **p<0.01. Units for blood flow are normalized and thus arbitrary units.
not associated with baseline pain threshold (r=–0.16, p=0.58; Abbreviation: SCD, sickle-cell disease.

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post-hypnosis pain threshold (median 46.3) was higher than
pre-hypnosis threshold (median 44.1) in the control group
(Z=–2.542, r=0.68; p=0.011), but pre- and post-hypnosis pain
threshold (median 43.8 and 45.5, respectively) did not differ in
the SCD group (Z=–0.722, r=0.21; p=0.43). Similarly, results
revealed that pain tolerance significantly increased following
hypnosis in the control group (t13=2.49, d=0.67; p=0.027),
but not in the SCD group (Z=–0.0408, r=0.097; p=0.72).
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period (trending toward significance, moderate effect size)
were larger in the SCD group compared to controls (t=3.152,
d=1.242, p=0.004; t=1.704, d=0.68, p=0.1; t=1.403, d=0.56,
p=0.18). Change in blood-flow amplitude during the pain-
intensity task was similar across groups (Table 3).
Discussion
The current pilot study assessed the effects of a brief hypnosis

Finally, post-hypnosis pain-intensity ratings (median 18.75)
were lower than pre-hypnosis ratings (median 26.25) in the
control group (Z=–2.275, r=–0.55; p=0.041). Post-hypnosis
pain-intensity ratings decreased in the SCD group, as indi-
cated by a moderate effect size, but did not reach statistical
significance (t13=–1.825, d=–0.49; p=0.091).
Aim 3: effects of hypnosis on peripheral
blood-flow responsiveness
A paired-sample t-test revealed that in the SCD group,
For personal use only.
session on acute experimental pain responses and peripheral
blood flow in adults with and without SCD. Overall, following
hypnosis, pain threshold and tolerance increased and pain
intensity decreased in the control group, and in the SCD
group peripheral blood flow increased to levels comparable
to controls. Pain-threshold and tolerance levels did not change
following hypnosis in patients with SCD, but a moderate
effect size showed decreased pain intensity in this group.
Acute-pain responsiveness

anticipation-period peripheral blood-flow amplitude was
significantly higher following hypnosis (t10=5.722, d=1.73;
p=0.0002). In the control group, there was no change between
pre- and post-hypnosis anticipation-period peripheral blood
flow (t12=–0.0207, d=0.06, p=0.84). There were no other
pre- and post-hypnosis differences in each task for either
group. See Table 2.
Aim 4: effect of hypnosis across groups
An independent-sample t-test across groups revealed that the
increases in blood-flow amplitude during post-hypnosis pain
task 1 – anticipation, pain task 1 (trending toward signifi-
cance, moderate effect size), and pain task 2 – anticipation
Examination of baseline pain responsiveness revealed that
there were no differences between controls and adults with
SCD in respect to pain threshold, tolerance, or intensity. We
found that following hypnosis, pain threshold and tolerance
significantly increased and pain intensity decreased in the
control group. Pain-threshold and tolerance levels did not
change following hypnosis in patients with SCD. There was
a trend toward decreased pain intensity in the SCD group,
and although this decrease was not statistically significant,
there was a moderate effect in the hypothesized direction.
Of note, based on previously published clinically significant
benchmarks for change in pain intensity, the mean decrease
in pain intensity in the control group reflected a minimally

Table 2 Effects of hypnosis flow on peripheral blood flow responsiveness

Control SCD
t p d t p d
Pre-hypnosis anticipation period –0.207 0.84 0.06 5.722 0.0002 1.73
Pre-hypnosis pain task –0.01 0.99 0.003 –0.587 0.57 0.18
Post-hypnosis anticipation period 0.187 0.85 0.05 1.294 0.23 0.39
Post-hypnosis pain task 0.255 0.8 0.07 0.719 0.49 0.22
Abbreviation: SCD, sickle-cell disease.

Table 3 Effect of hypnosis on peripheral blood flow

Change in blood-flow amplitude
Post-hypnosis period Control (n=13) SCD (n=11) t p d
Mean SD Mean SD
Pre-hypnosis anticipation period –0.01 0.068 0.06 0.042 –3.152 0.004 1.242
Pre-hypnosis pain task –0.01 0.049 0.02 0.035 –1.704 0.103 0.679
Post-hypnosis anticipation period –0.01 0.088 0.03 0.067 –1.403 0.175 0.561
Post-hypnosis pain task –0.01 0.026 0 0.076 –0.251 0.806 0.11
Abbreviation: SCD, sickle-cell disease.

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important change,23 whereas the SCD group did not reach this
threshold.24 This pilot study may have had insufficient power
to detect a significant effect, and there was limited variability
in pain scores across each group. Future work may benefit
from including a larger sample size to examine the clinically
significant effects of hypnosis on pain outcomes.
Another explanation for the lack of reduction in pain
thresholds and tolerance in the SCD group may be the
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presence of central sensitization resulting in persistent or
chronic pain. Persistent pain often experienced by individuals
with SCD2 may result in altered pain perception set points.
Modulation of neuronal activation thresholds have also
been observed via TRPV1 channels, which may translate to
changes in pain sensitivity to thermal stimuli21 and changes
in the central gain of the somatosensory system.22 However,
if patients with SCD are exposed to background chronic pain,
they may use a different reference point to indicate acute-pain
responses than those who do not have this experience with
For personal use only.
chronic pain. Pain thresholds may be set higher in patients
with SCD compared to controls, because of either past experi-
ences with significant pain during VOCs or because of under-
lying chronic pain and altered pain perception. Therefore, the
limited dose of treatment (ie, a single, brief hypnosis session)
may have not been sufficient to alter acute-pain thresholds
and tolerance in the face of altered peripheral and central
pain-modulation systems secondary to pain history or the
development of chronic pain. Future studies would benefit
from assessing pain history and the presence of chronic pain
to determine how these may affect acute-pain responsiveness.
Mechanisms of acute pain and chronic pain in patients with
SCD warrant further study.
Peripheral blood flow
Although pain responses in the SCD group did differ sig-
nificantly following hypnosis, the single hypnosis session
did have a significant effect on peripheral blood flow in
anticipation of and in response to pain stimulation in the
SCD group. At baseline, patients with SCD had significantly
lower blood flow than controls, but these levels increased to
levels comparable to the control group during post-hypnosis
tasks, erasing the group differences found at baseline. A
change in blood flow with hypnosis was not seen in the
control group. Hypnosis may produce analgesia by engaging
descending inhibitory pathways from the brain and increas-
ing regional blood flow.23 In the current study, we expected
blood flow in both groups to increase with hypnosis, but
blood flow increased only in the SCD group. In this study,
we demonstrated that hypnosis was beneficial in improving
Journal of Pain Research 2017:10
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Hypnosis on pain and blood flow in SCD
peripheral blood flow in anticipation of pain stimulation in
patients with SCD.
The current findings provide further support that patients
with SCD exhibit peripheral vascular system dysfunction.24
Our results indicate that a single brief hypnosis session may
activate top-down neuromodulatory mechanisms in patients
with SCD that result in increased vasodilation and peripheral
blood flow to a degree comparable to that of healthy controls.
Longitudinal research utilizing multiple hypnosis sessions
and continuous monitoring of blood flow in a larger sample is
warranted to examine the efficacy of hypnosis on blood flow
over time. Of interest is that peripheral blood flow increased
with hypnosis in anticipation of the pain event in SCD
patients, even without changes in reported pain responses.
Exploration of effects of hypnosis on pathways, such as the
autonomic nervous system (ANS), that can impact peripheral
blood flow but may not reach conscious awareness in patients
with SCD warrant further study.
Possible mechanisms
Considering possible mechanisms from a central perspective,
alterations in brain connectivity in inhibitory pain-control
networks have been observed during hypnosis.25,26 Specifi-
cally, increased connectivity between the ipsilateral insula
and bilateral dorsolateral prefrontal cortex has been observed
during hypnosis in healthy individuals who were highly
hypnotizable.25 In addition, decreased fractional amplitude
of low-frequency fluctuation in the dorsal anterior cingulate
cortex was observed in individuals who were highly hypnotiz-
able, a finding that may represent decreased attention to the
external environment during hypnosis25 and thus decreased
pain perception and responsiveness. Results from these
studies provide more evidence to support the concept that
hypnosis affects pain-modulatory systems, engages top-down
neuromodulatory pain circuits, and helps filter out external
stressors that may be contributing to allostatic stress load (ie,
pain and anticipation of pain). In the current study, although
no significant changes were observed in behavioral responses,
the increase in blood flow despite exposure to stress (ie, a
pain stimulus) may demonstrate this central pain-modulatory
mechanism.
In our sample, patients with SCD had lower baseline
peripheral blood flow compared to healthy controls, which is
consistent with other literature showing evidence of allostatic
load and ANS dysfunction in patients with SCD.27 In the cur-
rent study, following a single session of hypnosis, patients
with SCD exhibited increased peripheral blood flow in antici-
pation of and during pain tasks. This finding ­suggests that a
submit your manuscript | www.dovepress.com
1641
Dovepress
 Bhatt et al
single session of hypnosis may affect peripheral vascular pain
responses modulated by the ANS. Given that ANS-modulated
peripheral vasoconstriction with stress or pain may increase
likelihood for vaso-occlusion and VOCs,28–32 further examina-
tion of ANS mechanisms and neuromodulatory treatments
aimed at addressing pain-related autonomic regulation (eg,
hypnosis) is warranted.
Additional research is needed to understand the underly-
Journal of Pain Research downloaded from https://www.dovepress.com/ by 120.188.5.152 on 19-Sep-2018
ing mechanisms of the effects of hypnosis in patients with
SCD. Specifically, future studies should examine neurally
mediated systems, such as the ANS (eg, heart-rate vari-
ability and electrodermal activity), and central supraspinal
parameters (eg, brain imaging) to advance our understanding
of treatment effects and SCD pain-related pathophysiology
from a multisystem perspective. Tailoring neuromodulatory
interventions for the specific needs of patients with SCD
has the potential to improve treatment and patient outcomes.
For personal use only.
Limitations
Limitations in the study should be noted. First, the small
sample of this pilot study limited statistical power, and
findings may not generalize to larger samples or broader
populations. In addition, this pilot study did not include a
treatment-control condition, which limits our ability to assess
the success or unique effects of hypnosis. Future work should
include a treatment-control condition (eg, diaphragmatic
breathing, distraction) within a randomized controlled trial to
examine and confirm the specific effects of hypnosis. Future
studies may also compare hypnosis to other evidence-based
interventions, such as biofeedback, cognitive–behavioral
therapy, or therapeutic yoga.33 The current study did not
examine the effects of hypnosis on clinical pain outcomes
either, including the frequency and/or severity of VOCs, and
future work would benefit from assessing these outcomes
through longitudinal methodology. Further, it is possible that
more than a single hypnosis session is needed to affect change
in perception and behavioral responses to acute pain, and the
examination of the effects of multiple hypnosis sessions on
pain outcomes is warranted.
In the current study, baseline peripheral blood flow was
related to age in patients with SCD. This finding is not surpris-
ing, since we would expect that as individuals age they are
more prone to microvascular pathologies,34 which may impair
vascular function. Therefore, potential previous vascular dam-
age in our adult sample may have influenced baseline data and
treatment effects. Sampling of adolescents within a specific
age range in future studies may help control for potential
effects of microvascular damage on blood-flow outcomes.
1642 submit your manuscript | www.dovepress.com
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Dovepress
It is also important to note that only thermal sensory
testing was applied in the current study, and may not be
generalizable to all types of pain, as thermal pain has dif-
ferent underlying molecular mechanisms compared to other
types of pain.35 Additional covariates that may influence
ANS responsiveness and blood flow not included in the
current analyses (eg, pain history, SCD genotype, history of
VOCs, heart disease, anxiety, depression, smoking history,
and medication use) may have had an impact on the current
findings and should be assessed in future work. In addition,
the current study did not assess hypnotizability, which has
been shown to be associated with the effect of hypnosis on
autonomic response10 and vaso-occlusion.36 The inclusion of
qualitative post-hypnosis interviews in future work may help
further explore participants’ experiences and the effect of
hypnosis. Additionally, investigating the anticipation period
to unpainful stimuli would help address differences and
similarities in physiological responses. To help diminish the
effect of confounding variables, counterbalancing hypnotic
and nonhypnotic conditions may also help better isolate the
effect of hypnosis. Finally, the investigator and clinician in
the current study were not blinded to the patient condition,
which may have introduced bias. Future work will aim to
blind the investigator in the room or place the investigator
in a different room to collect psychophysiological measures.
Conclusion
This study demonstrated that the amount of peripheral blood
flow in anticipation of pain in adults with SCD increased
following a single, 30-minute hypnosis session. There was
a trend toward decreased perceived pain in SCD patients as
well. Given that peripheral vasoconstriction and blood flow
likely play a role in the development of VOCs, these findings
provide initial support for further study of mechanisms and
effects of neuromodulatory interventions in pain management
for patients with SCD. Collectively, our results suggest that
patients with SCD may need targeted treatment that addresses
both central and peripheral neurovascular processes. Future
work will determine if engagement in hypnotherapy affects
long-term pain and VOC outcomes in patients with SCD,
as well as examine pathways through which these effects
take place.
Author contributions
RRB was the primary author of manuscript and conducted
statistical analyses and interpretation of data. SRM was the
secondary author of the manuscript, interpreted data, and
provided expertise regarding sickle-cell disease. SE was
Journal of Pain Research 2017:10
 Dovepress
the lead developer of the hypnosis protocol and conducted
the hypnosis procedure with participants. KL assisted with
development of laboratory assessment and conducted labora-
tory assessments with participants. TDC provided expertise
regarding clinical aspects of sickle-cell disease. LKZ assisted
with development of the overall study protocol and provided
clinical expertise regarding the use of hypnosis for pain. JCT
provided expertise on laboratory pain assessment and was the
Journal of Pain Research downloaded from https://www.dovepress.com/ by 120.188.5.152 on 19-Sep-2018
lead developer of the laboratory pain protocol. All authors
contributed toward data analysis, drafting and revising the
paper and agree to be accountable for all aspects of the work.
Acknowledgment
This research was supported by the National Heart, Lung,
and Blood Institute (1U54HL117718 to TDC and LKZ).
Disclosure
The abstract of this paper was presented at the 2016 American
For personal use only.
Society of Hematology meeting as a poster with interim find-
ings. The authors report no conflicts of interest in this work.
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